This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Histone deacetylases (HDACs) are zinc-dependent hydrolytic enzymes involved in chromatin remodeling and play a critical role in the regulation of gene transcription via deacetylation of histone lysine residues. The small molecule HDAC inhibitor (HDI), suberoylanilide hydroxamic acid (SAHA;also known as Zolinza or Vorinostat) is currently in many clinical trials for cancer chemotherapy and holds great promise for the amelioration of other diseases as well. However, SAHA and other HDIs in development have molecular functionality and broad-spectrum activity with known pharmacokinetic difficulties and will certainly be problematic in the treatment of chronic illnesses. This research will develop new classes of HDIs and offer novel strategies for HDAC inhibition. Key to this project is the design of isozyme-specific HDIs based on competent models of the enzyme. Missing from current efforts in the development of HDIs is the availability of good models of the HDAC Class I isozymes from which to base drug design. This project combines both computational biochemistry and organic synthesis to achieve the goal of isozyme specificity in an HDI. A. Specific Aims Specific Aim 1: Design ixozyme-specific HDAC inhiitors with moderate potency for ideal therapeutic application using computational biochemistry methodologies. By selectively inhibiting individual HDAC isozymes, a better understanding of their role in disease states will be obtained. Currently the most promising HDAC inhibitors emerging from clincal trials have broad-spectrum activity and could pose future clinical issues. Key to this specific aim is the development of competent models for DHAC class I proteins based upon the crystal structure of HDAC8. Highly potent HDACi's have not been beneficial in clinical trials due to upregulation of many genes. We hypotehsize compounds with moderate potency, simliar to SAHA, and with isozyme specificity will be advantageous. Specific Aim 2: Synthesize and evaluate isozyme-specific HDAC inhibitors. A two-pronged approach will be undertaken. First, compounds with hydrophobic fingers to bind deeper in the active site of HDACs will be made based on already obtained preliminary results. Simultaneously, as new models are refinded, HDACi's will be designed to interact specifically with individual isozymes.